欧洲批准Valdoxan用于治疗重症抑郁症发作

欧洲委员会已经统一给予Servier公司的Valdoxan/Thymanax上市授权。这一批准是在大规模的国际开发计划包括几乎6000例成人抑郁患者短期和长期试验结果的基础之上进行的。该药品的活性成分称为agomelatine，是一种具有褪黑素能激动和5-HT能拮抗双重作用的药物，化学上是褪黑素的萘类似物。在作用机理上也是第一个褪黑素能抗抑郁药。在动物实验中，它有抗抑郁样和抗焦虑样性质，能促进睡眠，能使脱偶联的和时相变化的生物节律复偶联。临床试验中，以标准剂量25mg/日，也可增加到50mg/日，治疗重症抑郁患者，结果抑郁症状显著改善。与其它抗抑郁药比较显然一样有效，同时还有促进睡眠的作用（表现为缩短睡眠潜伏期，减少觉醒，改善睡眠稳定性），且不良反应较轻，有优良的安全性和耐受性。最常见的不良反应有头痛、鼻咽炎和胃肠道主诉，性功能障碍较SNRI显著减轻。在显著改善抑郁症状的同时能促进睡眠且安全性好是本品的主要特色和优点。

Valdoxan

1. NAME OF THE MEDICINAL PRODUCT
Valdoxan 25 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 25 mg of agomelatine.
Excipient: lactose monohydrate 61.84 mg
For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Film-coated tablet [tablet].
Orange-yellow, oblong, film-coated tablet with blue imprint of company logo on one side.

4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of major depressive episodes in adults

4.2 Posology and method of administration
The recommended dose is 25 mg once daily taken orally at bedtime.
After two weeks of treatment, if there is no improvement of symptoms, the dose may be increased to 50 mg once daily, i.e. two 25 mg tablets, taken together at bedtime.
Liver function tests should be performed in all patients : at initiation of treatment, and then periodically after around six weeks (end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase) and thereafter when clinically indicated (see also section 4.4).
Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free of symptoms.
Valdoxan tablets may be taken with or without food.

Children and adolescents:
Valdoxan is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy (see section 4.4).

Elderly patients:
Efficacy has not been clearly demonstrated in the elderly (≥ 65 years). Only limited clinical data is available on the use of Valdoxan in elderly patients ≥ 65 years old with major depressive episodes. Therefore, caution should be exercised when prescribing Valdoxan to these patients (see section 4.4).

Patients with renal impairment:
No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on the use of Valdoxan in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing Valdoxan to these patients.

Patients with hepatic impairment:
Valdoxan is contraindicated in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2).

Treatment discontinuation:
No dosage tapering is needed on treatment discontinuation.

4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Hepatic impairment (i.e. cirrhosis or active liver disease) (see sections 4.2 and 4.4).
Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) (see section 4.5).

4.4 Special warnings and precautions for use
Use in children and adolescents:
Valdoxan is not recommended in the treatment of depression in patients under 18 years of age since safety and efficacy of Valdoxan have not been established in this age group. In clinical trials among children and adolescents treated with other antidepressants, suicide-related behaviour (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed compared to those treated with placebo.

Use in elderly patients with dementia:
Valdoxan should not be used for the treatment of major depressive episodes in elderly patients with dementia since the safety and efficacy of Valdoxan have not been established in these patients.

Mania / Hypomania:
Valdoxan should be used with caution in patients with a history of mania or hypomania and should be discontinued if a patient develops manic symptoms.

Suicide/suicidal thoughts:
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo, in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Combination with CYP1A2 inhibitors (see sections 4.3 and 4.5)
Combination with potent CYP1A2 inhibitors is contraindicated. Caution should be exercised when prescribing Valdoxan with moderate CYP1A2 inhibitors (e.g. propranolol, grepafloxacine, enoxacine) which may result in increased exposure of agomelatine.

Increased serum transaminases:
In clinical studies, elevations of serum transaminases (>3 times the upper limit of the normal range) have been observed in patients treated with Valdoxan particularly on a 50 mg dose (see section 4.8). When Valdoxan was discontinued in these patients, the serum transaminases usually returned to normal levels. Liver function tests should be performed in all patients : at initiation of treatment and then periodically after around six weeks (end of acute phase), after around twelve and twenty four weeks (end of maintenance phase) and thereafter when clinically indicated. Any patient who develops increased serum transaminases should have his/her liver function tests repeated within 48 hours. Therapy should be discontinued if the increase in serum transaminases exceeds 3X upper limit of normal and liver function tests should be performed regularly until serum transaminases return to normal.
If any patient develops symptoms suggesting hepatic dysfunction liver function tests should be performed. The decision whether to continue the patient on therapy with Valdoxan should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed therapy should be discontinued.
Caution should be exercised when Valdoxan is administered to patients who consume substantial quantities of alcohol or who are treated with medicinal products associated with risk of hepatic injury.

Lactose intolerance:
Valdoxan contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction
Potential interactions affecting agomelatine:
Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and by CYP2C9/19 (10%). Medicinal products that interact with these isoenzymes may decrease or increase the bioavailability of agomelatine.
Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism of agomelatine resulting in a 60-fold (range 12-412) increase of agomelatine exposure.
Consequently, co-administration of Valdoxan with potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) is contraindicated.
Combination of agomelatine with oestrogens (moderate CYP1A2 inhibitors) results in a several fold increased exposure of agomelatine. While there was no specific safety signal in the 800 patients treated in combination with oestrogens, caution should be exercised when prescribing agomelatine with other moderate CYP1A2 inhibitors (e.g. propranolol, grepafloxacine, enoxacine) until more experience has been gained (see section 4.4).

Potential for agomelatine to affect other medicinal products:
In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in vivo nor the other CYP450 in vitro. Therefore, agomelatine will not modify exposure to medicinal products metabolised by CYP 450.

Medicinal products highly bound to plasma protein:
Agomelatine does not modify free concentrations of medicinal products highly bound to plasma proteins or vice versa.

Other medicinal products:
No evidence of pharmacokinetic or pharmacodynamic interaction with medicinal products which could be prescribed concomitantly with Valdoxan in the target population was found in phase I clinical trials: benzodiazepines, lithium, paroxetine, fluconazole and theophylline.

Alcohol:
The combination of Valdoxan and alcohol is not advisable.

Electroconvulsive therapy (ECT):
There is no experience of concurrent use of agomelatine with ECT. Animal studies have not shown proconvulsant properties (see section 5.3). Therefore, clinical consequences of ECT concomitant treatment with Valdoxan are considered to be unlikely.

4.6 Pregnancy and lactation
For agomelatine, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.
It is not known whether agomelatine is excreted into human milk. Agomelatine or its metabolites are excreted in the milk of lactating rats. Potential effects of agomelatine on the breast-feeding infant have not been established. If treatment with Valdoxan is considered necessary, breastfeeding should be discontinued.

4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
However, considering that dizziness and somnolence are common adverse reactions patients should be cautioned about their ability to drive a car or operate machinery.

4.8 Undesirable effects
In clinical trials, over 3,900 depressed patients have received Valdoxan.
Adverse reactions were usually mild or moderate and occurred within the first two weeks of treatment. The most common adverse reactions were nausea and dizziness.
These adverse reactions were usually transient and did not generally lead to cessation of therapy.
Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with Valdoxan.
Adverse reactions are listed below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The frequencies have not been corrected for placebo.

Nervous system disorders:
Common: headache, dizziness, somnolence, insomnia, migraine
Uncommon: paraesthesia

Eye disorders:
Uncommon: blurred vision

Gastrointestinal disorders:
Common: nausea, diarrhoea, constipation, upper abdominal pain

Skin and subcutaneous tissue disorders
Common: hyperhidrosis
Uncommon: eczema
Rare: erythematous rash

Musculoskeletal and connective tissue disorders
Common: back pain

General disorders and administration site conditions:
Common: fatigue

Hepato-biliary disorders:
Common increases (>3 times the upper limit of the normal range) in ALAT and/or ASAT (i.e. 1.1% on agomelatine 25/50 mg vs. 0.7 % on placebo).
Rare: hepatitis

Psychiatric disorders:
Common: anxiety
Frequency not known: Suicidal thoughts or behaviour (see section 4.4)

4.9 Overdose
There is limited experience with agomelatine overdose. During the clinical development, there were a few reports of agomelatine overdose, taken alone (up to 450 mg) or in combination (up to 525 mg) with other psychotropic medicinal products. Signs and symptoms of overdose were limited and included drowsiness and epigastralgia.
No specific antidotes for agomelatine are known. Management of overdose should consist of treatment of clinical symptoms and routine monitoring. Medical follow-up in a specialised environment is recommended.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antidepressants, ATC-code: NO6AX22
Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist. Binding studies indicate that agomelatine has no effect on monoamine uptake and no affinity for ¿, ¿ adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors.
Agomelatine resynchronises circadian rhythms in animal models of circadian rhythm disruption. Agomelatine increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin.
Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety.
In humans, Valdoxan has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.
The efficacy and safety of Valdoxan in major depressive episodes have been studied in a clinical programme including 5,800 patients of whom 3,900 were treated with Valdoxan.
Six placebo controlled trials have been performed to investigate the short term efficacy of Valdoxan in major depressive disorder: two flexible dose studies and four fixed dose studies. At the end of treatment (over 6 or 8 weeks), significant efficacy of agomelatine 25-50 mg was demonstrated in 3 of the six short-term double-blind placebo-controlled studies.
Agomelatine failed to differentiate from placebo in one study where the active control fluoxetine showed assay sensitivity. In two other studies, it was not possible to draw any conclusions because the active controls, paroxetine and fluoxetine, failed to differentiate from placebo.
Efficacy was also observed in more severely depressed patients (baseline HAM-D ¿ 25) in all positive placebo-controlled studies.
Response rates were statistically significantly higher with Valdoxan compared with placebo.
The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. Patients responding to 8/10-weeks of acute treatment with open-label Valdoxan 25-50 mg once daily were randomised to either Valdoxan 25-50 mg once daily or placebo for further 6-months. Valdoxan 25-50 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.0001) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow up period was 22% and 47% for Valdoxan and placebo, respectively.
Valdoxan does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with Valdoxan 25 mg increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Valdoxan 25 mg also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.
In a specific sexual dysfunction comparative study with remitted depressed patients, there was a numerical trend (not statistically significant) towards less sexual emergent dysfunction than venlafaxine for Sex Effects Scale (SEXFX) drive arousal or orgasm scores on Valdoxan. The pooled analysis of studies using the Arizona Sexual Experience Scale (ASEX) showed that Valdoxan was not associated with sexual dysfunction. In healthy volunteers Valdoxan preserved sexual function in comparison with paroxetine.
Valdoxan had neutral effect on body weight, heart rate and blood pressure in clinical studies.
In a study designed to assess discontinuation symptoms by the Discontinuation Emergent Signs and Symptoms (DESS) check-list in patients with remitted depression, Valdoxan did not induce discontinuation syndrome after abrupt treatment cessation.
Valdoxan has no abuse potential as measured in healthy volunteer studies on a specific visual analogue scale or the Addiction Research Center Inventory (ARCI) 49 check-list.

5.2 Pharmacokinetic properties
Absorption and bioavailability:
Agomelatine is rapidly and well (¿ 80%) absorbed after oral administration. Absolute bioavailability is low (< 5% at the therapeutic oral dose) and the interindividual variability is substantial. The bioavailability is increased in women compared to men. The bioavailability is increased by intake of oral contraceptives and reduced by smoking. The peak plasma concentration is reached within 1 to 2 hours.
In the therapeutic dose-range, agomelatine systemic exposure increases proportionally with dose. At higher doses, a saturation of the first-pass effect occurs.
Food intake (standard meal or high fat meal) does not modify the bioavailability or the absorption rate. The variability is increased with high fat food.

Distribution:
Steady state volume of distribution is about 35 l and plasma protein binding is 95% irrespective of the concentration and is not modified with age and in patients with renal impairment but the free fraction is doubled in patients with hepatic impairment.

Biotransformation:
Following oral administration, agomelatine is rapidly metabolised mainly via hepatic CYP1A2; CYP2C9 and CYP2C19 isoenzymes are also involved but with a low contribution.
The major metabolites, hydroxylated and demethylated agomelatine, are not active and are rapidly conjugated and eliminated in the urine.

Elimination:
Elimination is rapid, the mean plasma half-life is between 1 and 2 hours and the clearance is high (about 1,100 ml/min) and essentially metabolic.
Excretion is mainly (80%) urinary and in the form of metabolites, whereas unchanged compound recovery in urine is negligible.
Kinetics are not modified after repeated administration.

Renal impairment:
No relevant modification of pharmacokinetic parameters in patients with severe renal impairment has been observed (n=8, single dose of 25 mg), but caution should be exercised in patients with severe or moderate renal impairment as only limited clinical data are available in these patients (see section 4.2).

Hepatic impairment:
In a specific study involving cirrhotic patients with chronic mild (Child-Pugh type A) or moderate (Child-Pugh type B) liver impairment, exposure to agomelatine 25 mg was substantially increased (70-times and 140-times, respectively), compared to matched volunteers (age, weight and smoking habit) with no liver failure (see section 4.2, 4.3 and 4.4).

Ethnic groups:
There is no data on the influence of race on agomelatine pharmacokinetics.

5.3 Preclinical safety data
In mice, rats and monkeys sedative effects were observed after single and repeated administration at high doses.
In rodents, a marked induction of CYP2B and a moderate induction of CYP1A and CYP3A were seen from 125 mg/kg/day whereas in monkeys the induction was slight for CYP2B and CYP3A at 375 mg/kg/day. No hepatotoxicity was observed in rodents and monkeys in the repeat dose toxicity studies.
Agomelatine passes into the placenta and foetuses of pregnant rats.
Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility, embryofoetal development and pre- and post natal development.
A battery of in vitro and in vivo standard genotoxicity assays concludes to no mutagenic or clastogenic potential of agomelatine.
In carcinogenicity studies agomelatine induced an increase in the incidence of liver tumours in the rat and the mouse, at a dose at least 110-fold higher than the therapeutic dose. Liver tumours are most likely related to enzyme induction specific to rodents. The frequency of benign mammary fibroadenomas observed in the rat was increased with high exposures (60-fold the exposure at the therapeutic dose) but remains in the range of that of controls.
Safety pharmacology studies showed no effect of agomelatine on hERG (human Ether à-go-go Related Gene) current or on dog Purkinje cells action potential. Agomelatine did not show proconvulsive properties at ip doses up to 128 mg/kg in mice and rats.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:

•Lactose monohydrate
•Maize starch
•Povidone
•Sodium starch glycolate type A
•Stearic acid
•Magnesium stearate
•Silica, colloidal anhydrous
Film-coating:

•Hypromellose
•Yellow iron oxide (E172)
•Glycerol
•Macrogol
•Magnesium stearate
•Titanium dioxide (E171)
Printing ink containing shellac, propylene glycol and indigotine (E132) aluminium lake.

6.2 Incompatibilities
Not applicable.

6.3 Shelf life
3 years.

6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container
Aluminium/PVC blister packed in cardboard boxes (calendar).
Packs containing 7, 14, 28, 42, 56, 84 and 98 film-coated tablets.
Packs of 100 film-coated tablets for hospital use.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal
No special requirements.

7. MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
35, rue de Verdun
92284 Suresnes Cedex - France.
France

8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF THE FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
10 . DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

As prescribing information may vary from country to country, please refer to the complete data sheet supplied in your country.

valdoxan(阿戈美拉汀agomelatine)-全新作用机制的抗抑郁药
导读：褪黑索类似物阿戈美拉汀agomelatine,既是首个褪黑素受体激动剂，也是5-羟色胺2C(S-HTx)受体拮抗剂。动物试验与临床研究表明该药有抗抑郁、抗焦虑、调整睡眠节律及调节生物钟作用，同时其不良反应少，对性功能无不良影褪黑索类似物阿戈美拉汀agomelatine,既是首个褪黑素受体激动剂，也是5-羟色胺2C(S-HTx)受体拮抗剂。动物试验与临床研究表明该药有抗抑郁、抗焦虑、调整睡眠节律及调节生物钟作用，同时其不良反应少，对性功能无不良影响，也未见撤药反应.
首个褪黑素受体激动剂agomelatine(Valdoxan)为褪黑素类似物，它同时也是5一羟色胺2C(5-HTac)受体拮抗剂。褪黑素与其受体MT1和MT2的亲和力Ki分别为8.85x10-11及2.63x10-11，阿戈美拉汀与其相似，对克隆的人褪黑素受体MT1和MT2也有高度的亲和力(Ki分别为6.15X10"及2.68X10一，’)。此外，体外和体内试验显示，阿戈美拉汀对5一日几。也具有中度亲和力(IC50=2.7x10-7g/mol》.临床研究表明，阿戈美拉汀对抑郁症患者有较好的疗效，且不良反应非常少。
阿戈美拉汀由Servier公司开发研制，目前在注册上市前阶段。

——作用机制——
阿戈美拉汀抗抑郁的确切机制目前尚未明确单纯的5-HT2C。受体阻断剂并无抗抑郁作用阿戈美拉汀能阻断5-HT2C。受体，然而动物试验显示褪黑素也有少量的抗抑郁作用，并有研究发现应激与褪黑素分泌有关，但人体服用褪黑素并未见明显的抗抑郁作用。
另有研究表明，阿戈美拉汀抗抑郁的机制可能与增加海马部位神经元的可塑性及神经元增生有关。以免疫染色的方法测定成年大鼠脑部神经细胞的增生、再生及死亡，结果发现，阿戈美拉汀长期(3周)给药可增加海马腹侧齿状回细胞增生及神经元再生，而这一部位与情绪反映有关。但在急性或亚急性给药时(4小时或9周)未见类似情况。继续延长给药后，整个齿状回区域均出现细胞增生及神经元再生，表明阿戈美拉汀可不同程度地增加海马的神经再生，从而产生新的颗粒细胞。
抑郁症患者经常存在入睡困难、早醒或睡眠节律的改变，多导睡眠图常表现为慢波睡眠(SWS)减少、快速眼动睡眠(REM)密度增加或潜伏期减少、δ睡眠比例下降等。多数抗抑郁药物如三环类抗抑郁药(TCA)、选择性5一HT再摄取抑制剂(SSRI)等对REM有调节作用，但对非REM睡眠尤其是SWS效果较差。具有5一HT2受体阻断作用的某些药物如米安舍林(mianserine)、米氮平等有促进睡眠与改善睡眠持续性的作用，但其，阻断作用可造成宿睡、白天困倦等。阿戈美拉汀具有独特的药理机制即调节睡眠觉醒周期，因而可在晚间调节患者的睡眠结构增进睡眠。

——动物试验——
大量动物试验证明阿戈美拉汀具有抗抑郁、抗焦虑及调整睡眠周期循环节律的作用。
由于阿戈美拉汀与褪黑素的关系，人们很早便开始注意到其具有的调节动物昼夜周期作用。啮齿类动物注射阿戈美拉汀，可减轻其时差反应闭。之后研究发现阿戈美拉汀还具有杭抑郁、抗焦虑作用，如转基因鼠动物模型试验[3]提示，阿戈美拉汀具有类似地昔帕明(去甲丙咪喇的抗抑郁效果，以及与褪黑素类似的对昼夜循环节律的调整作用。大鼠慢性轻微压力(CMS)的抑郁动物模型试验[4]提示，连续周持续给予阿戈美拉汀(10和50mg/kg腹腔注射)可逆转由CMS诱导的食糖量减少，其效应呈剂量依赖性、以同等剂量给药1Omglkg腹腔注射)时阿戈美拉汀作用强度和持续时间与丙咪嚓或氟西汀相似。针对大鼠强迫游泳的另一项抑郁动物模型试验问提示，单次或13日内持续给予阿戈美拉汀均能减少模型鼠的不动时间。持续给药时阿戈美拉汀能显示出剂量依赖性的抗抑郁效应。习得性无助模型试验161提示，连续5日给予模型鼠阿戈美拉汀一日1次1Omglkg,能改善其回避学习的缺陷，这一效应与丙咪唑相似。3项有关焦虑的动物模型试验冈提示，早晚给予阿戈美拉汀(10一75mg/kg》可增加动物在高架十字迷宫试验和Vogel饮水冲突致焦虑模型试验中的反应性，而晚间给予同等剂量的褪黑素仅可增加动物张臂探索，对Vogel试验无反应，条件性超声发声试验显示，模型动物早晚给予阿戈美拉汀可改善焦虑症状而褪黑素无类似效果。这些结果均提示阿戈美拉汀具有抗焦虑效应。另一项动物强迫游泳试验的结果显示阿戈美拉汀可加强地西伴的抗焦虑作用。

——临床疗效——
多项临床研究证实阿戈美拉汀具有明显的抗抑郁作用，且起效较快，对抑郁以及伴随的焦虑症状均有较好的疗效。
2002年Lov等进行的一项为期8周的国际多中心安慰剂对照研究，比较了固定剂量阿戈美拉汀与帕罗西汀的疗效。符合美国精神障碍诊断和统计手册第四版(DSM-IV)抑郁障碍(MDD)诊断标准的711例患者入组该研究，患者年龄18--65岁。患者在使用安慰剂，周后(以排除快速安w剂起效者)分别接受阿戈美拉汀一日1、5或25mg,或帕罗西汀一日20mg或继续接受安慰剂治疗。这些患者治疗前汉密顿抑郁r_-表(HAMD)评分和蒙哥马利抑郁量表(MADRS)评分分别为27.4和31.5分，组间无显著差异。治疗8周后，与安慰剂组相比，HAMID及MADRS终末平均分评价显示，阿戈美拉汀25mg组和帕罗西汀组均具有显著的抗抑郁疗效(P<0.05).并且阿戈美拉汀25mg组的起效时间较安慰剂组早(P'=0.008)，服药第周便可见组间显著差异(P<0.05)，而帕罗西汀组直到第4周才观察到与安慰剂组的差异。
该研究还对抑郁伴焦虑症状作了评估，与安慰剂组相比，阿戈美拉汀25mg组和帕罗西汀组均能明显降低汉密顿焦虑量表(HAMA)分值(P<0.05)，提示阿戈美拉汀可能与帕罗西汀类似，能改善MDD患者伴随的焦虑情绪。该研究对HAMD分值≥25的患者进行再分析显示，与安慰剂组相比，阿戈美拉汀25mg组疗效显著{P<0.05},而帕罗西汀组与安慰剂组相比并无显著差异(P=0.09).提示阿戈美拉汀对较为严重的MDD的疗效可能优于帕罗西汀等SSRI.

2005年Olie进行的2项双盲安慰剂平行对照研究，MDD患者随机接受阿戈美拉汀一日25mg或安慰剂，2周后病情改善不明显者剂量增加至一日50mg,为期6周，结果表明，阿戈美拉汀疗效明显优于安慰剂，药物剂量增加至一日50mg者2周后获得类似疗效，并且耐受性良好.
2007年另一项双盲安慰剂平行对照研究也获得了相似的结果。该研究共纳入238例中重度MID患者，息者随机接受阿戈美拉汀(一日25mg,晚上服，2周后若疗效欠佳则加量至一日50m9)或安慰剂，疗程6周。评定标准为HAMD，临床总体印象量表改善项目(CGI一I)和临床总体印象量表严重程度项目(CGI一S)评分，结果显示，阿戈美拉汀疗效显著优于安慰剂，以HAMD终末分值相比较，阿戈美拉汀组与安慰剂组两组差异为3.44(P<0.001)，CGI一I及CGI一s评分也显示，阿戈美拉汀组优于安慰剂组(组间差异分别为4.45和0.50,P值均为0.006).两组有效率分别为54.3%对35.5%(P<0.05);起效时间阿戈美拉汀组也早于安慰剂组(P=0.008).对重度抑郁症患者也有类似结果。另外，HAMD量表的情绪与睡眠项评分也显示阿戈美拉汀组优于安慰剂组。阿戈美拉汀耐受性好，两个剂量组均显示与安慰剂相似的安全性。
Pjrek等进行的一项标签开放性研究证实，阿戈美拉汀对季节性情感障碍也有效。给予37例急性抑郁发作的季节性情感障碍患者晚间服用阿戈美拉汀一日25mg，为期14周，以HAMD等级量表结构式访谈指导(SIGH一SAD)、CGI-S、CGI-I、Circscreen量表(对睡眠以及生理节律紊乱进行自评的量表)及轻度躁狂量表进行评定。结果显示，2周后患者的SIGH-SAD、CGI-S,CGI-I评分即显著下降(P<0.001);Circscreen评分在治疗过程中也获得显著改善(P<0.001)，轻度躁狂量表评分无明显变化.治疗14周75.7%患者达临床好转(SIGH一SAD评分低于50%的基础评分)，70.3%达临床痊愈(SIGH一SAD评分低于8))，仅，例出现乏力的不良反应。

——对睡眠的影响——

褪黑素对睡眠以及生物周期节律有调节作用，阿戈美拉汀是否也有类似的作用引起人们的关注，尤其是很多抑郁症患者均存在睡眠障碍。动物试验已证实阿戈美拉汀具有与褪黑素类似的调节睡眠的作用。一项针对门诊MDD患者的研究比较了阿戈美拉汀一日25--5Omg与文拉法辛一日75一15Dmg的疗效，结果显示，两者治疗抑郁疗效类似，但阿戈美拉汀在Leeds睡眠评估问卷(LSEQ)量表的2项评分(入睡和睡眠质量)上较文拉法辛改善明显，并且观察发现，这种对睡眠的改善作用在用药1周时即显现，且对白天的警觉性无影响。

另一项标签开放性研究评估了阿戈美拉汀对MDD患者睡眠结构的影响。15例HAMD评分≥20的门诊MDD患者服用阿戈美拉汀一日25mg,为期42日，在第7,14,42日分别进行睡眠多导研究。结果显示，治疗42日患者的睡眠效率、睡后醒转次数及SW5总量均有改善，SWS在开始的那个睡眠周期改善尤为显著。从第7日起，SWS在最开始的4个睡眠循环中减少，在14日以前，δ波的比例增加。REM潜伏期、总量及密度均未见改变。提示阿戈美拉汀增加睡眠的连续性与质量，使在睡眠周期循环中的分配及6波的强度正常化。安全性与耐受性

——安全性与耐受性——

阿戈美拉汀不良反应较少，常见的有头痛、恶心和乏力等.不管是短期治疗还是长期维持治疗，其不良反应发生率与安慰剂相似，并且长期治疗的不良反应较短期治疗更少一些，这也与安慰剂相似。阿戈美拉汀不引起体重的改变，也很少有胃肠道不良反应，Loo等同进行的临床研究显示，帕罗西汀组恶心发生率为17%，安慰剂组为4.3%，而阿戈美拉汀25mg组仅为2.9%,统计学检验显示阿戈美拉汀与安慰剂组相似，而与帕罗西汀组有显著差异。阿戈美拉汀对肝脏功能、肾脏功能、心电图等均无影响。

抗抑郁药物对性功能的影响已引起相当的重视，TCA、SSRI、选择性5-HT及去甲肾上腺素再摄取抑制剂(SNRI)等均存在对性功能不同程度的影响，但阿戈美拉汀对性功能的影响较小。与文拉法辛相比，阿戈美拉汀组性功能的各项心理与躯体症状评定均优于文拉法辛。
2004年Montgomery等目进行7一项有关撤药的双盲安慰剂对照研究，MDD患者在双盲条件下接受阿戈美拉汀一日25mg或帕罗西汀一日20mg治疗，然后192例获得持续缓解的患者随机进入继续治疗组或安慰剂组，为期2周，在第1、2周分别对停药后出现的症状及体征量表(DESS)进行评定，结果发现，继用阿戈美拉汀和停用阿戈美拉汀的两组间DESS评分无显著差异，表明阿戈美拉汀几无停药反应，而帕罗西汀组在停药后第1周即出现明显的失眠、头晕、恶心和肌痛等反应，这些反应在第2周时消失.
——结论——
阿戈美拉汀为首个褪黑素受体激动剂，具有良好的抗抑郁效果。其起效较快，对抑郁及其伴随的焦虑、失眠等症状均有较好的疗效，且不良反应少，安全性高，为临床治疗MDD提供了新方法。

【-原产地英文商品名-】Valdoxan 25mg/tablet 28tablets/box
【-原产地英文药品名-】:Agomelatine
【-原产地英文化合物名称-】N-[2-(7-Methoxy-1-napthyl)ethyl]acetamide
【-中文参考商品-】Valdoxan 25毫克/片 28片/盒
【-中文参考药品-】阿戈美拉汀
【-中文参考化合物名称-】阿戈美拉汀
【-曾用名-】Melitor, Thymanax
临床试验期-】完成
【-中文适应病症参考-】抑郁
【-中文适应病症参考-】焦虑
【-中文适应病症参考-】成人抑郁
【-生产厂家中文参考-】法国Servier Laboratories公司
【-生产厂家英文名-】Servier Laboratories, France